MbSOD in chemotherapeutic-Induced Cardiac Injury

空间 但前提是。 心脏病是使用蒽环类药物进行癌症治疗的一个主要剂量限制因素 协议的一部分。活性氧物种(ROS)的产生与一种 治疗药物的数量，包括那些包含氧化还原循环基团的药物。这项研究的目标是 确定在癌症治疗过程中导致心脏保护的新机制。我们对动物的研究 分离的心肌细胞表明线粒体抗氧化酶的过度表达 含锰超氧化物歧化酶对阿霉素诱导的心脏损伤的保护作用 心脏损伤。有趣的是，ADR治疗导致循环中肿瘤坏死因子水平的增加 α(肿瘤坏死因子)是一种多效性细胞因子，也已被证明能产生ROS。我们还发现ADR- 心肌损伤与P53移位到线粒体及其与线粒体的相互作用有关 MnSOD型。根据这些新的发现，我们假设ADR毒性是一个级联反应的结果 涉及ADR产生直接的氧化应激，从而导致肿瘤坏死因子的产生和放大 线粒体中的氧化应激。为了验证这一假说，从 MnSOD缺陷型、野生型和过表达MnSOD以及P53缺陷型、P53缺陷型小鼠 相同近交系背景的MnSOD缺陷型和P53缺陷型过表达的小鼠 用作模特。目标1和目标2将检验以下假设：ADR毒性是由 涉及ADR及其代谢物产生直接氧化应激，从而导致肿瘤坏死因子的产生 以及心脏组织和心肌细胞中氧化应激的放大。目标3将检验这一假设 线粒体中启动的氧化应激起到死亡信号的作用，它调节P53易位和 其线粒体介导的转录依赖和独立途径。目标4将测试 细胞抗氧化状态或肿瘤坏死因子水平的选择性调节改变ADR诱导的心脏的假说 实验治疗环境中的创伤。这些研究的结果将为以下方面提供重要的见解 减少癌症治疗相关心脏损伤的机械性药物干预。 由于ADR的广泛使用，翻译这些发现不仅会提高生活质量，而且 也将提高大量癌症患者的无癌生存概率。

SPACE PROVIDED. Heart disease is a major dose limiting factor of cancer therapy that uses anthracycline as a component of the protocol. Generation of reactive oxygen species (ROS) has been implicated in the toxicity of a large number of therapeutic agents including those containing the redox cycling groups. The goal of this study is to identify novel mechanisms that lead to cardioprotection during cancer treatment. Our studies of animal and isolated cardiomyocytes indicate that overexpression of the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) protects the heart against adriamycin (ADR)-induced cardiac injury. Interestingly, ADR treatment leads to an increase in circulating levels of tumor necrosis factor alpha (TNF)t a pleiotropic cytokine that has also been shown to produce ROS. We also found that ADR- induced cardiac injury is associated with translocation of p53 to the mitochondria and interaction of p53 with MnSOD. Based on these novel findings we hypothesize that ADR toxicity is the result of a cascade that involves ADR producing direct oxidative stress that sequentially leads to TNF production and amplification of oxidative stress in mitochondria. To test this hypothesis, cardiac tissue and cardiomyocytes isolated from MnSOD deficient, wild type, and mice overexpressing MnSOD as well as p53 deficient, p53 deficient with MnSOD deficient, and p53 deficient overexpressing MnSOD mice of the same inbred background will be used as models. Aims 1 and 2 will test the hypothesis that ADR toxicity is the result of a cascade that involves ADR and its metabolites producing direct oxidative stress that sequentially leads to TNF production and amplification of oxidative stress in heart tissues and in cardiomyocytes. Aim 3 will test the hypothesis that oxidative stress initiated in mitochondria serves as a death signal, which regulates p53 translocation and its mitochondrial-mediated transcription dependent and independent pathways . Aim 4 will test the hypothesis that selective modulation of cellular antioxidant status or TNF levels alters ADR-induced cardiac njury in experimental therapeutic settings. The results from these studies will provide important insights for mechanistic-based pharmacological interventions to reduce cancer therapy-associated cardiac injury. Because the extensive use of ADR, translation of these findings will not only improve the quality of life but will also enhance the probability of cancer free survival for a large number of cancer patients.